This proposal addresses the problem of drug resistance in HIV-1 protease, an enzyme essential to the maturation of HIV infection to Acquired Immunodeficiency Syndrome (AIDS). Unique HIV-1 protease constructs with mutations known to cause drug resistance will be studied using a combination of Electron Paramagnetic Resonance (EPR), Nuclear Magnetic Resonance (NMR), and a host of biochemical and molecular biological analysis techniques. The constructs will be characterized in terms of structural properties, functional properties, enzymatic activity, and drug resistance. The expected outcome is to determine a relationship between enzyme structure, function, activity, and drug resistance that can be used to understand the problem of drug resistance from a functional perspective and aid in devising new strategies for treatment of HIV infection on a global scale. Another major goal of this funding opportunity is to provide a diverse training environment for the funded individual to aid in preparation for a career as a significantly productive independent researcher.